Vaccination with antigens that are expressed in a broad spectrum of histologically distinct unrelated tumor cell types would be highly desirable. The polypeptide component of telomerase, also know as telomerase reverse transcriptase or TERT, is an attractive candidate for a broadly expressed tumor antigen since telomerase is silent in normal tissues but is reactivated in over 85% of cancers. The primary objective of this application is to test the hypothesis that telomerase can function as a broadly useful tumor rejection antigen, namely that vaccination against telomerase can generate protective immunity against a wide range of unrelated tumors. The proposed studies will be carried out using murine tumor models.
The specific aims of this application are: 1) to determine whether vaccination against murine telomerase using dendritic cells transfected with telomerase RNA will induce CTL and engender protective immunity against histologically distinct tumors of unrelated origin, 2) to explore the hypothesis and the mechanism underlying the immunosubdominant nature of telomerase as antigen (see Preliminary Data section), 3) to explore strategies to augment the antitumor response elicited by vaccination with telomerase RNA transfected DC. Here the applicant will test the hypothesis that stimulating a telomerase-specific CD4 T cell response, T-help, is necessary for generating an optimal anti-telomerase CTL and anti-tumor immune response and will explore combination therapies to enhance the anti-telomerase and anti-tumor response generated by vaccination with telomerase RNA transfected DC. 4) The last specific aim is to evaluate two additional candidates for broadly expressed tumor rejection antigens: Oncofetal antigen (OFA) and filamin-1. The long term objective of this project is to identify several broadly expressed tumor antigens, which in combination will provide an effective and widely applicable treatment to cancer patients. The studies proposed in this application will provide the foundations for this ambitious goal.
